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Gut CD4s May Not Recover After HAART
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Guts and Monkeys and Monkey's guts: HIV pathogenesis seen through an endoscope
CROI, Feb 2007, Los Angeles
Written By David Margolis, MD, University of North Carolina
Most immune cells live in tissue, only occasionally migrating to perambulate in the bloodstream. And 98% our immune cells live in the tissue where we contact the outside world: in the skin and the mucosal tissue, most notably the roughly 30-foot long stretch of our small and large intestine that contains 50% of our immune cells.
Some years ago Ron Veazey observed a prompt and profound depletion of CD4 cells in the intestinal mucosa of SIV-infected monkeys. The recognition in the last 2 years or so that the human immune system takes a tremendous slug in the gut in the first few weeks of infection has completely revised current paradigms of the progression of HIV infection to AIDS.
Gut CD4s recover after ART:
Shenefelt presented a study of the recovery of CD4 cells in gut-associated lymphoid tissue in patients given ART (abstr. 28;
http://www.retroconference.org/
2007/Abstracts/29705.htm). Previous studies suggest that reconstitution of CD4+ T cells in antiretroviral therapy (ART)-treated individuals is less complete in GALT than in peripheral blood.
14 drug-naive patients were started on ART containing nevirapine, abacavir, AZT, and 3TC. CD4 cell counts at initiation were < 100/µl in all. Of the 14 enrollees, only 3 women and 5 men remained in the study, 6 others were lost to follow-up. Viremia was suppressed to <50 copies/ml in all but one subject at week 48, who still had low-level viremia. CD4 cell counts increased in all to ca. 200 cells/µl.
Differing with prior studies of GALT and the effect of ART, 4-_m sections of GALT biopsies taken from the colon were stained with CD3 and CD4 antibodies, and counted by immunofluorescent microscopy. Numbers of lamina propria CD4+ T cells/mm3 were calculated. Mean GALT CD4+ T cells/mm3 were 279 at baseline, as expected higher than that in peripheral blood. Mean GALT CD4+ T cells increased through week 24 to 890 cells/mm3. This increase was greater than that observed in peripheral blood. Mean GALT CD4+ T cells decreased to 759 cells/mm3 at week 48, but remained significantly different than baseline and still reflected a larger increase than in peripheral blood. These increases in CD4+ T cells are significantly larger in GALT than peripheral blood, particularly during the first 24 weeks of therapy, a finding of immune reconstitution that has not been seen in other studies.
However, during the Q&A the study was criticized on methodological grounds. Mehandru from the Aaron Diamond pointed to a study their group had just published (Mehandru S et al. Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection. PLoS Med. 2006; 3:e484), in which patients treated as early as 2 weeks after acute HIV infection, and for up to 7 years did not have full CD4 reconstitution as measured by both microscopy and flow cytometry of colonic GALT biopsy samples.
Most gut CD4s do not recover after most ART:
A similar study presented by Estes (Abstr. 67) presented a more nuanced picture. This group compared lymphocytes populations in inguinal lymph nodes and ileal biopsies in 32 HIV-infected and 11 uninfected volunteers. After ART was given, second biopsies were obtained after 6 months in 15 of the HIV+ patients. Total, naive, central and effector memory CD4 populations in were measured in peripheral blood, lymph nodes, Peyers patches, and lamina propria using flow cytometry and quantitative microscopy.
As expected, CD4 cells were depleted wherever Estes and colleagues looked prior to the initiation of ART. There were significant increases in CD4+ cells after 6 months of ART in peripheral blood and lymph node, but not in the ileal lamina propria. However, in Peyers patches, the inductive site where naive and central memory CD4+ T cells in GALT reside, there was a significant increase in central memory CD4+ T cells unless ART had been delayed until the patient had late stage disease (stated as clinical AIDS, but clinical details not presented). On the other hand, if therapy was started in the acute/early increases in central memory CD4+ T cells were the greatest. As clinical details were not given, it was unclear to this author how much reconstitution could be expected in GALT central memory cells if ART was initated according to current guidelines.
Estes said that lymphatic tissues do not uniformly reconstitute CD4+ T cells with ART. Lymph node and Peyers patches are capable of limited reconstitution. This was most striking for central memory CD4 cells in Peyers patches.
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